Colorectal cancer (CRC) is a leading cause of cancer mortality in the U.S. Family history, a predictor of CRC risk, is considered a surrogate for genetic variation in susceptibility. This familial association exists even in the absence of major gene effects such as the role of the loss-of-function mutations in DNA MisMatch Repair (MMR) genes in inherited CRC. As has been extensively characterized for other DNA repair pathways, it is hypothesized that variation among individuals in MMR capacity is a common genetic trait and that modest reduction in MMR capacity contributes to the familial component of variation in sporadic CRC risk. In this proposal, we focus on (1) developing a quantitative functional assay that integrates the impact of variants in the proteins (genes) of the MMR pathway on the activity of the pathway, (2) validating that the assay has sufficient specificity, sensitivity and repeatability to be deployed in population-based studies and (3) obtaining a preliminary estimate of the extent of variation existing among individuals in capacity of the MMR pathway to repair damaged DNA. This study of variation in MMR capacity will employ 120 lymphoblastoid cell lines from previously collected, population based samples. 60 samples will be from CRC cases with a profile consistent with elevated contributions of genetic variation to risk - age at diagnosis of less than 60 years and family history of CRC. This group is expected to be enriched for individuals with reduced MMR capacity. The other 60 samples will be unaffected individuals without a family history of CRC. Development and validation of the MMR capacity assay and obtaining preliminary estimates of variation provides methodology and preliminary data for future studies to confirm that reduced MMR capacity is a common genetic susceptibility factor contributing to elevated risk of CRC. The availability of a biomarker of susceptibility to exposure(s) will be of benefit to identify groups of individuals contributing disproportionately to colorectal cancer incidence in the general population. Substantial reductions in the morbidity and mortality from colorectal cancer and cost of care are best achieved by focusing educational programs encouraging lifestyle modification, early detection screening programs and preventive interventions on this group. [unreadable] [unreadable] [unreadable]